Polymersomes, 50 nm-50 μm diameter vesicles formed from amphiphilic block copolymers, have attracted much attention due to their superior mechanical stabilities and unique chemical properties when compared to conventional lipid-based vesicles (liposomes) and micelles. (See, generally, Discher, D. E.; Eisenberg, A. Science, 2002, 297, 967-973; Discher, B. M.; Won, Y. Y.; Ege, D. S.; Lee, J. C. M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Science 1999, 284, 1143-1146; Lee, J. C. M.; Bermudez, H.; Discher, B. M.; Sheehan, M. A.; Won, Y. Y.; Bates, F. S.; Discher, D. E. Biotechnol. Bioeng. 2001, 73, 135-145, Bermudez, H.; Brannan, A. K.; Hammer, D. A.; Bates, F. S.; Discher, D. E., Macromolecules 2002, 35, 8203-8208, and Ghoroghchian, P. P.; Frail, P. R.; Susumu, K.; Blessington, D.; Brannan, A. K.; Bates, F. S.; Chance, B.; Hammer, D. A.; Therien, M. J. P NATL ACAD SCI USA, 2005, 102, 2922-2927.) Polymersomes are typically stronger than liposomes, have greater membrane thickness, and can be heavily PEGylated. (Discher, B. M.; Won, Y. Y.; Ege, D. S.; Lee, J. C. M.; Bates, F. S.; Discher, D. E.; Hammer, D. A. Science, 1999, 284, 1143-1146, Bermudez, H.; Brannan, A. K.; Hammer, D. A.; Bates, F. S.; Discher, D. E. Macromolecules, 2002, 35, 8203-8208.) Polymer vesicles have further proven capable of not only entrapping water-soluble hydrophilic compounds (drugs, vitamins, fluorophores, etc.) inside of their aqueous cavities but also hydrophobic molecules within their thick lamellar membranes. For instance, bacteriorhodopsin, ATP synthase, and hemoglobin have all been reconstituted within the aqueous core. (Choi, H. J.; Montemagno, C. D. Nano Letters, 2005, 5, 2538-2542, Arifin, D. R.; Palmer, A. F. Biomacromolecules, 2005, 6, 2172-2181.) Within the hydrophobic membrane, a variety of porphyrin-derived fluorophores have been incorporated at very high dye loadings, delivered intravenously to mice, and observed by in vivo fluorescence imaging. (Ghoroghchian, P. P.; Lin, J. J.; Brannan, A. K.; Frail, P. R.; Bates, F. S.; Therien, M. J.; Hammer, D. A. Soft Matter, 2006, 2, 973-980, Ghoroghchian, P. P.; Frail, P. R.; Susumu, K.; Blessington, D.; Brannan, A. K.; Bates, F. S.; Chance, B.; Hammer, D. A.; Therien, M. J. P NATL ACAD SCI USA, 2005, 102, 2922-2927, Christian, N. A.; Milone, M. C.; Ranka, S. S.; Li, G. Z.; Frail, P. R.; Davis, K. P.; Bates, F. S.; Therien, M. J.; Ghoroghchian, P. P.; June, C. H.; Hammer, D. A. Bioconjugate Chemistry, 2007, 18, 31-40.) Moreover, the size, membrane thickness, and stabilities of these synthetic vesicles can be rationally tuned by selecting block copolymer chemical structure, number-average molecular weight, hydrophilic to hydrophobic volume fraction, and via various preparation methods. (See Bhargava, P.; Tu, Y. F.; Zheng, J. X.; Xiong, H. M.; Quirk, R. P.; Cheng, S. Z. D. J. Am. Chem. Soc. 2007, 129, 1113-1121, Ortiz, V.; Nielsen, S. O.; Klein, M. L.; Discher, D. E. J POLYM SCI POL PHYS, 2006, 44, 1907-1918.) Polymersomes thus have many attractive characteristics that lend to their potential application in medical imaging, drug delivery, and cosmetic devices. (See, Discher, D. E.; Eisenberg, A. Science, 2002, 297, 967-973, Frail, P. R.; Susumu, K.; Blessington, D.; Brannan, A. K.; Bates, F. S.; Chance, B.; Hammer, D. A.; Therien, M. J. P NATL ACAD SCI USA, 2005, 102, 2922-2927 and Meng F.; Engbers, G. H. M.; Feijen J. Journal of Controlled Release, 2005, 101, 187-198.)
Lisposomes have been studied as delivery systems for therapeutic agents. (U.S. Pat. No. 4,891,043.) Early studies described the use of heat to release material encapsulated in lipid vesicles. Microwaves have been applied to heat specific tissue areas after the injection of heat-sensitive lipid vesicles. The major drawback of the use of microwaves is that microwaves cannot be focused as they have long wavelengths, and therefore they tend to damage surrounding tissues. In addition, microwaves indiscriminately heat up both the liposomes and the surrounding tissues, and since microwaves are non-visible electromagnetic energy they cannot be aimed at the target tissues accurately. The use of lipid vesicles for delivery of material in the body is disclosed in several patents. (U.S. Pat. No. 4,310,506 to Baldeschwieler et al; U.S. Pat. No. 4,350,676 to Laties et al; U.S. Pat. No. 4,515,736 to Deamer; U.S. Pat. No. 4,522,803 to Lenk et al.; and U.S. Pat. No. 4,610,868 to Fountain et al.) Due to the drawbacks of employing microwave energy, the use of laser light to rupture lipid vesicles was studied. The use of a system employing a laser to rupture laser light-absorbing and heat-sensitive lipid vesicles which thereby release the drugs or dyes encapsulated therein is disclosed in U.S. Pat. No. 4,891,043 to Zeimer et al.
The drawback of employing lipid vesicles for intracorporeal delivery of therapeutic agents is that lipid vesicles lack strength and durability. Researchers have turned to polymer vesicles as favored candidates for targeted delivery of therapeutic agents. Pioneering efforts to manipulate the morphology of polymer vesicles using external stimuli have recently been described including reversible, temperature-dependent vesicles which interchange between morphologies. (Geng, Y.; Discher, D. E. J. Am. Chem. Soc., 2005, 127, 12780-12781, Qin, S. H.; Geng, Y.; Discher, D. E.; Yang, S. Advanced Materials, 2006, 18, 2905, Bhargava, P.; Tu, Y. F.; Zheng, J. X.; Xiong, H. M.; Quirk, R. P.; Cheng, S. Z. D. J. Am. Chem. Soc., 2007, 129, 1113-1121.) New methods for externally modulating polymersome structure and function would greatly expand the utility of these organic materials for applications in engineering and biomedicine.
PCT/US2006/038189, filed Sep. 28, 2006, teaches, inter alia, poly(ethyleneoxide)-b-polycaprolactone (PEO-b-PCL) diblock copolymers that are biodegradable and/or bioresorbable. PCT/US2007/00621, filed Jan. 10, 2007, teaches, inter alia, polymersomes containing multi[(porphinato)metal] compounds having proquinoidal spacer units. PCT/US2004/024014, filed Jul. 26, 2004, discloses, among other things, polymersomes having photo-emissive agents dispersed within the polymersome membrane. PCT/US2004/024014 also teaches polymersomes having photo-emissive agents dispersed within the polymersome membrane. U.S. Pat. No. 6,835,394, issued on Dec. 28, 2004, is directed to polymersomes and related encapsulating membranes with extensive covalent cross-linking of the membrane, and methods of controlling release of the encapsulating material. U.S. Pat. No. 7,217,427, issued on May 15, 2007 sets forth, inter alia, polymersomes and related encapsulating membranes with extensive covalent cross-linking of the membrane, and methods of encapsulating material in the polymersome. All of these materials are incorporated herein by reference.
There remains a need for polymersomes that can respond selectively to an external stimulus in order to deliver a cargo to target cells or tissues. Such cargo may be therapeutic, analgesic, diagnostic or otherwise useful in the treatment, palliation or diagnosis of disease.